Aldehyde dehydrogenase

Aldehyde dehydrogenases (EC 1.2.1.3) are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)–H) to carboxylic acids (R–C(=O)–O–H). The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

Aldehyde dehydrogenase is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids. There are three different classes of these enzymes in mammals: class 1 (low K_m, cytosolic), class 2 (low K_m, mitochondrial), and class 3 (high K_m, such as those expressed in tumors, stomach, and cornea). In all three classes, constitutive and inducible forms exist. ALDH1 and ALDH2 are the most important enzymes for aldehyde oxidation, and both are tetrameric enzymes composed of 54 kDa subunits. These enzymes are found in many tissues of the body but are at the highest concentration in the liver.

The active site of the aldehyde dehydrogenase enzyme is largely conserved throughout the different classes of the enzyme and, although the number of amino acids present in a subunit can change, the overall function of the site changes little. The active site binds to one molecule of an aldehyde and one molecule of either NAD⁺ or NADP⁺, which functions as a cofactor. Cysteine and glutamate molecules interact with the aldehyde substrate. Many other residues will interact with NAD(P)⁺ to hold it in place. Magnesium may be used to help the enzyme function, although the degree to which magnesium assists the enzyme varies between different classes of aldehydes.

The overall reaction catalysed by the aldehyde dehydrogenases is:

In this NAD(P)⁺-dependent reaction, the aldehyde enters the active site through a channel extending from the surface of the enzyme. The active site contains a Rossmann fold, and interactions between the cofactor and the fold allow for the action of the active site.

A sulfur from a cysteine in the active site makes a nucleophilic attack on the carbonyl carbon of the aldehyde. The hydrogen is kicked off as a hydride and attacks NAD(P)⁺ to make NAD(P)H. The enzyme's active site then goes through an isomorphic change whereby the NAD(P)H is moved, creating room for a water molecule to access the substrate. The water is primed by a glutamate in the active site, and the water makes a nucleophilic attack on the carbonyl carbon, kicking off the sulfur as a leaving group.

Researchers at the University of Tsukuba found that durian extract inhibited aldehyde dehydrogenase activity, lending credence to an Asian folklore warning against consuming durian with alcohol.

ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during alcohol oxidation. In this pathway (ethanol to acetaldehyde to acetate), the intermediate structures can be toxic, and health problems arise when those intermediates cannot be cleared. When high levels of acetaldehyde occur in the blood, facial flushing, lightheadedness, palpitations, nausea, and general "hangover" symptoms occur. These symptoms are indicative of a medical condition known as the alcohol flush reaction, also known as "Asian flush" or "Oriental flushing syndrome".